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| | ==Identification of a novel FXR ligand that regulates metabolism== | | ==Identification of a novel FXR ligand that regulates metabolism== |
| - | <StructureSection load='4wvd' size='340' side='right' caption='[[4wvd]], [[Resolution|resolution]] 2.90Å' scene=''> | + | <StructureSection load='4wvd' size='340' side='right'caption='[[4wvd]], [[Resolution|resolution]] 2.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4wvd]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=4ii6 4ii6]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4WVD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4WVD FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4wvd]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4WVD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4WVD FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=IVM:(2AE,4E,5S,6S,6R,7S,8E,11R,13R,15S,17AR,20R,20AR,20BS)-6-[(2S)-BUTAN-2-YL]-20,20B-DIHYDROXY-5,6,8,19-TETRAMETHYL-17-OXO-3,4,5,6,6,10,11,14,15,17,17A,20,20A,20B-TETRADECAHYDRO-2H,7H-SPIRO[11,15-METHANOFURO[4,3,2-PQ][2,6]BENZODIOXACYCLOOCTADECINE-13,2-PYRAN]-7-YL+2,6-DIDEOXY-4-O-(2,6-DIDEOXY-3-O-METHYL-ALPHA-L-ARABINO-HEXOPYRANOSYL)-3-O-METHYL-ALPHA-L-ARABINO-HEXOPYRANOSIDE'>IVM</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.9Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ii6|4ii6]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=IVM:(2AE,4E,5S,6S,6R,7S,8E,11R,13R,15S,17AR,20R,20AR,20BS)-6-[(2S)-BUTAN-2-YL]-20,20B-DIHYDROXY-5,6,8,19-TETRAMETHYL-17-OXO-3,4,5,6,6,10,11,14,15,17,17A,20,20A,20B-TETRADECAHYDRO-2H,7H-SPIRO[11,15-METHANOFURO[4,3,2-PQ][2,6]BENZODIOXACYCLOOCTADECINE-13,2-PYRAN]-7-YL+2,6-DIDEOXY-4-O-(2,6-DIDEOXY-3-O-METHYL-ALPHA-L-ARABINO-HEXOPYRANOSYL)-3-O-METHYL-ALPHA-L-ARABINO-HEXOPYRANOSIDE'>IVM</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NR1H4, BAR, FXR, HRR1, RIP14 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4wvd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wvd OCA], [https://pdbe.org/4wvd PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4wvd RCSB], [https://www.ebi.ac.uk/pdbsum/4wvd PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4wvd ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4wvd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4wvd OCA], [http://pdbe.org/4wvd PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4wvd RCSB], [http://www.ebi.ac.uk/pdbsum/4wvd PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4wvd ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/NCOR1_HUMAN NCOR1_HUMAN]] Mediates transcriptional repression by certain nuclear receptors. Part of a complex which promotes histone deacetylation and the formation of repressive chromatin structures which may impede the access of basal transcription factors.<ref>PMID:14527417</ref> [[http://www.uniprot.org/uniprot/NR1H4_HUMAN NR1H4_HUMAN]] Ligand-activated transcription factor. Receptor for bile acids such as chenodeoxycholic acid, lithocholic acid and deoxycholic acid. Represses the transcription of the cholesterol 7-alpha-hydroxylase gene (CYP7A1) through the induction of NR0B2 or FGF19 expression, via two distinct mechanisms. Activates the intestinal bile acid-binding protein (IBABP). Activates the transcription of bile salt export pump ABCB11 by directly recruiting histone methyltransferase CARM1 to this locus.<ref>PMID:10334992</ref> <ref>PMID:10334993</ref> <ref>PMID:12815072</ref> <ref>PMID:15471871</ref> <ref>PMID:12718892</ref> <ref>PMID:18621523</ref> <ref>PMID:19410460</ref> <ref>PMID:19586769</ref> | + | [https://www.uniprot.org/uniprot/NCOR1_HUMAN NCOR1_HUMAN] Mediates transcriptional repression by certain nuclear receptors. Part of a complex which promotes histone deacetylation and the formation of repressive chromatin structures which may impede the access of basal transcription factors.<ref>PMID:14527417</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 4wvd" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 4wvd" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Art:Opening a Gate to Human Health|Art:Opening a Gate to Human Health]] |
| | + | *[[Bile acid receptor 3D structures|Bile acid receptor 3D structures]] |
| | + | *[[Nuclear receptor corepressor|Nuclear receptor corepressor]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Li, Y]] | + | [[Category: Large Structures]] |
| - | [[Category: Wang, R]] | + | [[Category: Li Y]] |
| - | [[Category: Af-2 helix]] | + | [[Category: Wang R]] |
| - | [[Category: Bar]]
| + | |
| - | [[Category: Bile acid receptor]]
| + | |
| - | [[Category: Corepressor]]
| + | |
| - | [[Category: Ligand binding pocket]]
| + | |
| - | [[Category: Nhr]]
| + | |
| - | [[Category: Nr1h4]]
| + | |
| - | [[Category: Nuclear receptor]]
| + | |
| - | [[Category: Three-layer helical sandwich]]
| + | |
| - | [[Category: Transcription]]
| + | |
| - | [[Category: Transcription regulation]]
| + | |
| - | [[Category: Transcription regulator fxr]]
| + | |
| Structural highlights
Function
NCOR1_HUMAN Mediates transcriptional repression by certain nuclear receptors. Part of a complex which promotes histone deacetylation and the formation of repressive chromatin structures which may impede the access of basal transcription factors.[1]
Publication Abstract from PubMed
Farnesoid X receptor (FXR) has important roles in maintaining bile acid and cholesterol homeostasis. Here we report that the antiparasitic drug ivermectin is a ligand for nuclear FXR. We identify ivermectin using a high-throughput compound library screening and show that it induces the transcriptional activity of the FXR with distinctive properties in modulating coregulator recruitment. The crystal structure of ivermectin complexed with the ligand-binding domain of FXR reveals a unique binding mode of ivermectin in the FXR ligand-binding pocket, including the highly dynamic AF-2 helix and an expanded ligand-binding pocket. Treatment of wild-type mice, but not of FXR-null mice, with ivermectin decreases serum glucose and cholesterol levels, suggesting that ivermectin regulates metabolism through FXR. Our results establish FXR as the first mammalian protein targeted by ivermectin with high selectivity. Considering that ivermectin is a widely used clinical drug, our findings reveal a safe template for the design of novel FXR ligands.
The antiparasitic drug ivermectin is a novel FXR ligand that regulates metabolism.,Jin L, Feng X, Rong H, Pan Z, Inaba Y, Qiu L, Zheng W, Lin S, Wang R, Wang Z, Wang S, Liu H, Li S, Xie W, Li Y Nat Commun. 2013;4:1937. doi: 10.1038/ncomms2924. PMID:23728580[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Yoon HG, Chan DW, Reynolds AB, Qin J, Wong J. N-CoR mediates DNA methylation-dependent repression through a methyl CpG binding protein Kaiso. Mol Cell. 2003 Sep;12(3):723-34. PMID:14527417
- ↑ Jin L, Feng X, Rong H, Pan Z, Inaba Y, Qiu L, Zheng W, Lin S, Wang R, Wang Z, Wang S, Liu H, Li S, Xie W, Li Y. The antiparasitic drug ivermectin is a novel FXR ligand that regulates metabolism. Nat Commun. 2013;4:1937. doi: 10.1038/ncomms2924. PMID:23728580 doi:10.1038/ncomms2924
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